Clinical Trial of Estrogen for Postpartum Depression

Postpartum-related mood disorders cause significant distress to a potentially large number of
women. The demand for effective therapies for treating these mood disorders is considerable,
as is the need to define clinical or biologic markers that may predict successful response of
these mood disturbances to estradiol. Despite the prevalence of postpartum depressions, only
a few double-blind, controlled trials of antidepressant agents have been performed in this
condition (1-4)- only two of which were placebo-controlled. A recent large multicenter trial
failed to confirm the initially promising but anecdotal reports of the protective role of
fish oil in PPD (5). Similarly, despite evidence of estradiol s therapeutic efficacy in
trials

that were both open (monotherapy) (6) and controlled (combined with traditional
antidepressant agents (7)), the potential of estradiol to be an effective alternative to
traditional psychotropics in postpartum depression has not been examined under controlled
conditions.

Postpartum depressions occur by definition after delivery when women are relatively
hypogonadal. Indeed, plasma estradiol and progesterone levels are low and comparable to those
seen during the peri and postmenopause. However, there is no evidence that postpartum
depression represents a simple hormone deficiency, and women with postpartum depression are
not distinguished from women without postpartum depression on the basis of any abnormality of
basal reproductive hormones. Nonetheless, a role for declining estradiol secretion has been
suggested by the following observations: 1) estradiol therapy has been reported to have a
prophylactic effect in women at high risk for developing postpartum depression (8),
suggesting that the prevention of a decline in estradiol levels (threshold or rate of
decline) may prevent the onset of postpartum depression in some women; and (2) declining
ovarian steroids trigger the onset of mood disturbances in women with but not women without a
history of postpartum depression during a scaled down model of pregnancy in the puerperium
(9). Thus, as with depressions occurring during the perimenopause, when ovarian hormone
secretion is also declining, postpartum depression may also be responsive to estradiol
therapy. In fact, open trials of estradiol therapy in postpartum depression (6) as well as a
trial of estradiol in combination with traditional antidepressants (7) have suggested that
estradiol does have antidepressant-like effects that are observed within a three week time
period in women with postpartum onset major depression. Thus, estradiol treatment may not
only provide a safe and effective alternative to traditional antidepressants in women with
postpartum depression, but it may also suggest the relevant hormonal trigger for the
development of this condition.

In this protocol we wish to investigate the effects of estradiol on mood in women with
moderately severe postpartum depression under placebo controlled conditions. This protocol
will address the following question: 1) Does estradiol improve mood in postpartum depressed
women?

- INCLUSION CRITERIA:

1. A history of at least two weeks with postpartum-related mood disturbances of
moderate severity, and self-report of the onset of depression within three months
of a normal vaginal delivery or uncomplicated Caesarean section;

2. A current episode of minor (meeting 3-4 criterion symptoms) or major depression
(of moderate severity or less on the SCID severity scale and not meeting DSM-IV
criteria symptom 9 [suicidal ideation]) as determined by the administration of
the minor depression module of the SADS-L and the Structured Clinical Interview
for DSM-IV. Additionally, to ensure that subjects meet a minimum threshold for
severity of depression, subjects will have scores greater than or equal to 10 on
either the Beck Depression Inventory (BDI) or the Center for Epidemiologic
Studies - Depression (CES-D) Scale during at least three of the six clinic visits
during the two week screening phase, as well as a 17 item Hamilton Depression
score greater than or equal to 10. Subjects will be excluded if they meet any of
the following criteria: major depression of greater than moderate severity
(including postpartum psychosis). DSM-IV criteria #9 (suicidal ideation), or
anyone requiring immediate treatment after clinical assessment.

3. Not greater than six months post delivery;

4. Age 20 to 45;

5. In good medical health, and not taking any medication or dietary and herbal
supplements on a regular basis (with the exception of multivitamins or calcium
supplements).

EXCLUSION CRITERIA:

The following conditions will constitute contraindications to treatment and will preclude a
subject s participation in this protocol:

1. severe major depression with any of the following:

- positive (threshold) response to SCID major depression section item # 9, suicidal
ideation;

- anyone requiring immediate treatment after clinical assessment;

- severity ratings greater than moderate on the SCID IV interview (including
postpartum psychosis);

2. current treatment with antidepressant medications

3. history of psychiatric illness during the two years before the reported onset of the
current episode of depression or a history of either mania (DSM-IV criteria) or
postpartum psychosis at any time in the past.

4. history of ischemic cardiac disease, pulmonary embolism, retinal thrombosis, or
thrombophlebitis; any subject with risk factors for thrombo-embolic phenomena
including cigarette smokers (greater than 10 cigarettes per day), varicose veins,
patients with prolonged periods of immobilization (including prolonged travel), and
active heart disease.

5. renal disease, asthma

6. hepatic dysfunction

7. women with a history of carcinoma of the breast, or women with a family history of the
following: premenopausal breast cancer or bilateral breast cancer in a first degree
relative; multiple family members (greater than three relatives) with postmenopausal
breast cancer

8. women with a history of uterine cancer, endometriosis, ill-defined pelvic lesions,
particularly undiagnosed ovarian enlargement, undiagnosed vaginal bleeding

9. patients with a known hypersensitivity to estradiol, transdermal skin patches, or
medroxyprogesterone acetate

10. pregnant women

11. porphyria

12. diabetes mellitus

13. cholecystitis or pancreatitis

14. history of cerebrovascular disease (stroke), epilepsy, hypertension, hypercalcemia

15. recurrent migraine headaches

16. malignant melanoma

17. history of familial hyperlipoproteinemia

18. prior hormonal therapy for the treatment of postpartum-related mood or physical
symptoms within the last six months

19. history of psychiatric illness during the two years prior to the reported onset of the
current episode of depression